RECENT FINDINGS:[unreadable] USING THE DIVERGENCE OF L1 INSERTS TO DETERMINE THE MUTATION RATE - The neutral mutation rate is equal to the base substitution rate when the latter is not affected by natural selection. Differences between these rates may reveal that factors such as natural selection, linkage, or a mutator locus are affecting a given sequence. We examined the neutral base substitution rate by measuring the sequence divergence of 30,000 pairs of inactive orthologous L1 retrotransposon sequences interspersed throughout the human and chimpanzee genomes. In contrast to other studies, we related orthologue divergence to the time (age) that the L1 sequences resided in the genome prior to the chimpanzee and human speciation. As expected, the younger orthologues contained more hypermutable CpGs than the older ones because of their conversion to TpGs (and CpAs). Consequently, the younger orthologues accumulated more CpG mutations than the older ones during the 5 Myr since the human and chimpanzee lineages separated. But during this same time, the younger orthologues also accumulated more non-CpG mutations than the older ones. In fact, non-CpG and CpG mutations showed an almost perfect (R2 = 0.98) correlation for 97% of the orthologue pairs. The correlation is independent of C + G content, recombination rate, and chromosomal location. Therefore, it likely reflects an intrinsic effect of CpGs, or mutations thereof, on non-CpG DNA rather than the joint manifestation of the chromosomal environment. The CpG effect is not uniform for all regions of non-CpG DNA. Therefore, the mutation rate of non-CpG DNA is contingent to varying extents on local CpG content. Aside from their implications for mutational mechanisms, these results indicate that a precise determination of a uniform genome-wide neutral mutation rate may not be attainable. We now have extended these studies to include all primate specific L1 families that first emerged 80 - 100 Myr ago. These studies showed that for families older than 50 Myr the decrease in CpG content with age begins to level off and that below a certain threshold, mutations at CpG sites have little effect on the non-CpG mutation rate. We also showed that the effect of CpG mutations on the non-CpG mutation rate extends undiminished for about 100 bp to either side of the CpG. By identifying a set of orthologues whose divergence is minimally if at all affected by CpG mutations we were able to determine to what extent DNA replication determined mutation rate. This determination depends on comparing the divergence of orthologues on autosomes with that of those on the sex chromosomes, because male and female gametes undergo significantly different numbers of cell divisions (DNA replications). Although the divergence of the L1 orthologues on the Y chromosome was higher than the orthologue divergences on the X chromosome or autosomes, it was not nearly as high expected from the estimated differences between female and male germline cell divisions in humans and chimpanzees. Thus DNA replication may not be the major factor that determines the neutral mutation rate in primates.